Abstract
Fluorescence imaging is an emerging clinical technique for real-time intraoperative visualization of tumors and their boundaries. Though multiple fluorescent contrast agents are available in the basic sciences, few fluorescence agents are available for clinical use. Of the clinical fluorophores, delta aminolevulinic acid (5ALA) is unique for generating visible wavelength tumor-specific fluorescence. In 2017, 5ALA was FDA-approved for glioma surgery in the United States. Additionally, clinical studies suggest this agent may have utility in surgical subspecialties outside of neurosurgery. Data from dermatology, OB/GYN, urology, cardiothoracic surgery, and gastrointestinal surgery show 5ALA is helpful for intraoperative visualization of malignant tissues in multiple organ systems. This review summarizes data from English-language 5ALA clinical trials across surgical subspecialties. Imaging systems, routes of administration, dosing, efficacy, and related side effects are reviewed. We found that modified surgical microscopes and endoscopes are the preferred imaging devices. Systemic dosing across surgical specialties range between 5 and 30 mg/kg bodyweight. Multiple studies discussed potential for skin irritation with sun exposure, however this side effect is infrequently reported. Overall, 5ALA has shown high sensitivity for labeling malignant tissues and providing a means to visualize malignant tissue not apparent with standard operative light sources.
Highlights
Surgeons have utilized light to better visualize their surgical fields since antiquity
Delta-aminolevulinic acid generates this fluorescence by causing tumor-specific accumulation of the fluorescent molecule protoporphyrin IX (PpIX)
Fewer studies to date have evaluated the use of 5ALA for squamous cell carcinomas (SCC), though these studies have shown that 5ALA has potential for improve visualization of SCC
Summary
Surgeons have utilized light to better visualize their surgical fields since antiquity. Stummer et al studied the efficacy of 0.2, 2, and mg/kg in a total of patients with HGGs and demonstrated that a 10-fold increase in dosage from 2 to 20 mg/kg yielded only a 4-fold increase in signal They concluded that a dose higher than 20 mg/kg was unlikely to yield significant benefits. They concluded that a dose of up to 50 mg/kg was safe in patients and suggested that higher doses of 5ALA may increase tumor fluorescence, their results were not statistically significant in their small sample population Considering these results, most groups, including Stummer et al. Eljamel et al concluded that 5ALA fluorescence was useful in pituitary adenomas of various subtypes [26] These studies offer encouraging evidence that 5ALA fluorescence may be applicable to other intracranial tumors and may further help neurosurgeons visualize tumors in the operating room. To increase depth penetration of excitation light, Roberts et al recently demonstrated that using red-light excitation (620–640 nm) and a sensitive spectrallyresolved camera to take advantage of 5ALA’s second, smaller excitation/emission peak, neoplastic areas could be visualized up to 5 mm below the tissue surface [28]
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